Chronic kidney disease (CKD) is a major health problem with increasing incidence and prevalence, high costs, and poor outcomes. Introduction of the Kidney Disease Outcome Quality Initiative (K/DOQI) classification and the use of estimated glomerular filtration rate (eGFR) to assess renal function have identified large numbers of patients with previously undiagnosed CKD (National Kidney Foundation. Am J Kidney Dis 2002; 39 (2 Suppl 1): S1-266; Centers for Disease Control and Prevention (CDC), Morb Mortal Wkly Rep 2007; 56: 161-165). However, only a minority of CKD patients ever advance to end-stage renal disease (ESRD) (Clase et al., BMJ 2004; 329: 912-915). The identification of those patients with the greatest risk for CKD progression remained a challenge. Through the adoption of the K/DOQI recommendations and routinely reported estimates of GFR by many laboratories, substantial success has been achieved in screening for undiagnosed CKD. However, there is an urgent need for further risk stratification and the identification of further risk predictors to target interventions to those patients with CKD most likely to progress to ESRD.
Amino-terminal proBNP (NT-proBNP), a well established prognostic marker for cardiovascular disease, has been shown to predict kidney disease progression in non-diabetic patients with primary CKD (Spanaus et al., Clin Chem 2007; 53: 1264-1272).
A-type natriuretic peptide (ANP) and adrenomedullin (ADM) are potent hypotensive, diuretic, and natriuretic peptides involved in maintaining cardiovascular and renal hemostasis (Vesely et al., Cardiovasc Res 2001; 51: 647-658; Bunton et al., Pharmacol Ther 2004; 103: 179-201). Increased plasma concentrations of ANP and ADM have been reported in patients with cardiovascular disease and in patients with kidney disease (Lerman et al., Lancet 1993; 341: 1105-1109; Jougasaki et al., Circulation 1995; 92:286-289; Winters et al., Biochem Biophys Res Commun 1988; 150: 231-236; Ishimitsu et al., J Clin Invest 1994; 94: 2158-2161). However, ANP and ADM have never been considered as markers to predict the progression of kidney disease.
The peptide Adrenomedullin (ADM) was first described in 1993 (Kitamura et al. (1993), Biochem. Biophys. Res. Commun. 192:553-560) as a novel hypotensive peptide comprising 52 amino acids, which had been isolated from a human pheochromocytoma. In the same year, cDNA coding for a precursor peptide comprising 185 amino acids and the complete amino acid sequence of this precursor peptide were also described (Kitamura et al. (1993), Biochem. Biophys. Res. Commun. 194:720-725). The precursor peptide, which comprises, inter alia, a signal sequence of 21 amino acids at the N-terminus, is referred to as “pre-pro-Adrenomedullin” (pre-pro-ADM).
The ADM peptide comprises amino acids 95 to 146 of pre-pro-ADM, from which it is formed by proteolytic cleavage. Some peptide fragments of those formed in the cleavage of the pre-proADM have been characterized in detail, in particular the physiologically active peptides adrenomedullin (ADM) and “PAMP”, a peptide comprising 20 amino acids (22-41) which follow the 21 amino acids of the signal peptide in pre-proADM. Another fragment of unknown function and high ex vivo stability is midregional proAdrenomedullin (MR-proADM) (Struck et al. (2004), Peptides 25(8):1369-72), for which a reliable quantification method has been developed (Morgenthaler et al. (2005), Clin. Chem. 51(10):1823-9).
The discovery and characterization of ADM in 1993 triggered intensive research activity and a flood of publications, the results of which have recently been summarized in various review articles, in the context of the present description, reference is being made in particular to the articles to be found in an issue of “Peptides” devoted to ADM (Peptides 22 (2001)), in particular (Takahashi (2001), Peptides 22, 1691 and Eto (2001), Peptides 22, 1693-1711). The subject is further reviewed in Hinson et al. (Hinson et al. (2000), Endocr. Rev. 21 (2), 138-167). ADM may be regarded as a polyfunctional regulatory peptide. It is released into the circulation in an inactive form extended by a C-terminal glycine (Kitamura et al. (1998), Biochem. Biophys. Res. Commun. 244 (2), 551-555).
ADM is an effective vasodilator. The hypotensive effect has been associated particularly with peptide segments in the C-terminal part of ADM. Peptide sequences of the N-terminus of ADM on the other hand exhibit hypertensive effects (Kitamura et al. (2001), Peptides 22, 1713-1718).
Atrial natriuretic peptide (ANP, also known as atrial natriuretic factor (ANF)) is a peptide hormone comprising 28 amino acid residues (SEQ ID NO:8). The ANP gene comprises 3 exons and 2 introns and codes for a 153 amino acid pre-proANP (SEQ ID NO:6). Upon cleavage of an N-terminal signal peptide (25 amino acids) and the two C-terminal amino acids (127/128), proANP is released. ANP comprises residues 99-126 from the C-terminus of the precursor prohormone proANP (SEQ ID NO:7). This prohormone is cleaved into the mature 28 amino acid peptide ANP, also known as ANP (1-28) or α-ANP, and the amino terminal fragment ANP (1-98) (NT-proANP, SEQ ID NO:9). Thus, NT-proANP and ANP are produced in equimolar amounts. The 98 amino acid NT-proANP may be further processed proteolytically. Mid-regional proANP (MR-proANP) is defined as proANP or any fragments thereof comprising at least amino acid residues 53-90 of proANP. Amino acids 53 to 90 of proANP are illustrated in SEQ ID NO:10 (FIG. 10). Measurement of MR-proANP has been used in differential diagnosis of acute decompensated heart failure (Gegenhuber et al., Clin Chem 2006; 52: 827-31).
Concerning ANP and precursors and fragments thereof, several publications deal with measurements of these analytes in patients with advanced kidney disease, in particular before and after hemodialysis. In these publications the measured levels of analytes are analyzed with respect to their association to other parameters, which have been obtained from the patients at the same time as the samples were obtained for measurement. None of the publications has followed the development of the disease over time, and thus cannot and does not make investigations on whether an analyte level measured at a given time point is associated with an increase in the severity of the disease, i.e. whether an analyte level can be suitable for the prediction of the progression of the disease. Nephron. 1991; 58(1):17-22. Change in plasma immunoreactive N-terminus, C-terminus, and 4,000-dalton midportion of atrial natriuretic factor prohormone with hemodialysis. Winters C J, Vesely D L. Regul Pept Supp1.1985; 4:110-2. Plasma concentration of atrial natriuretic polypeptide in chronic hemodialysis patients. Yamamoto Y, Higa T, Kitamura K, Tanaka K, Kangawa K, Matsuo H.